Sepsis kills more than 215,000 Americans each year. It is estimated that 750,000 Americans are infected with severe sepsis and 29% of them die from it each year. Sepsis deaths make 9% of all death cases in the U.S. Sepsis kills as many Americans as myocardial infections, even more than traffic accidents.
Two to three million Americans acquire a hospital infection each year and 10% of these infections progress to sepsis. More than 90,000 of these patients die from sepsis infected in hospitals.
Severe sepsis and septic shock (severe sepsis combined with low blood pressure) took up to 135,000 lives each year in the intensive care units (ICU) in the European Union according to the OECD Health Report of 2000. In Britain, 5,000 out of 100,000 patients who acquired a hospital infection die from sepsis every year in acute care hospitals belonging to the NHS organisation.
The death toll has increased year after year due to the fact that the number of patients predisposed to sepsis, such as the elderly, premature neonates, and cancer patients, has increased, not least because many serious illnesses are more treatable than before. Also the use of invasive medical devices and aggressive procedures has increased.
Gram-negative bacteria cause more than 40% of all septicemic infections and many of the Gram-negative bacteria are extremely multiresistant. Gram-negative bacteria provide a harder challenge in therapy than Gram-positives, as they possess a unique structure, the outer membrane, as their outermost structure. Lipopolysaccharide molecules located on the outer membrane inhibit the diffusion of many antibacterial agents deeper into the cell, where their ultimate targets are located. More than 95% of the novel antibacterial agents isolated from nature or chemically synthesized in 1972-1991 lacked activity against Gram-negatives (Vaara 1993).
Polymyxins are a group of closely related antibiotic substances produced by strains of Paenibacillus polymyxa and related organisms. These cationic drugs are relatively simple peptides with molecular weights of about 1000. Polymyxins, such as polymyxin B, are decapeptide antibiotics, i.e. they are made of ten (10) aminoacyl residues. They are bactericidal and especially effective against Gram-negative bacteria such as Escherichia coli and other species of Enterobacteriaceae, Pseudomonas, Acinetobacter baumannii, and others. However, polymyxins have severe adverse effects, including nephrotoxicity and neurotoxicity. These drugs thus have limited use as therapeutic agents because of high systemic toxicity.
Polymyxins have been used in the therapy of serious infections caused by those bacteria, but because of the toxicity, their use was largely abandoned in the 70's when newer, better tolerated antibiotics were developed. The recent emergence of multiresistant strains of Gram-negative bacteria has necessitated the therapeutic use of polymyxins as the last resort, in spite of their toxicity, and as many of the less toxic antibiotics have already lost their effectiveness against particular strains of the said bacteria, the use of polymyxins has again increased.
Accordingly, polymyxins have now been recalled to the therapeutic arsenal, although, due to their toxicity, on a very limited scale. Their systemic (i.e. non-topical) use is, however, largely restricted to the therapy of life-threatening infections caused by multiply resistant strains of Ps. aeruginosa and A. baumannii as well as by carbapenem-resistant enteric bacteria.
Polymyxins consist of a cyclic heptapeptide part and a linear part consisting of a tripeptide portion and a hydrophobic fatty acid tail linked to the α-amino group of the N-terminal amino acid residue of the tripeptide and may be represented by the general formula:

wherein R1-R3 represent the tripeptide side chain portion; R4-R10 the heptapeptide ring portion and R(FA) represents the hydrophobic fatty acid tail linked to the α-amino group of the N-terminal amino acid residue of the tripeptide.
The polymyxin group includes the following polymyxins: A1, A2, B1-B6, C, D1, D2, E1, E2, F, K1, K2, M, P1, P2, S, and T (Storm et al. 1977; Srinivasa and Ramachandran 1979). All polymyxins are polycationic and possess five (5) positive charges, with the exception of polymyxin D, F, and S which possess four (4) positive charges. It should be noted that modified polymyxins that lack the fatty acid part R(FA) but carry R1-R10 have one additional positive charge when compared to the natural polymyxins they derived from, due to the free α-amino group in the N-terminus of the derivative. Accordingly, for example, such a derivative of polymyxin B or polymyxin E carries six (6) positive charges in total.
The clinically used polymyxin B and polymyxin E differ from each other only in the residue R6, which is D-phenylalanyl residue in polymyxin B and D-leucyl residue in polymyxin E.
Also circulin A and B are classified as polymyxins (Storm et al. 1977). They differ from other polymyxins only in carrying isoleucyl residue in the position R7 whereas other polymyxins have either threonyl or leucyl residue in the said position. For an overview of the structures of some polymyxins, see Table 1.
TABLE 1The structure of selected polymyxins and octapeptin as well as selected derivatives thereofCompoundR(FA)R1R2R3R4R5R6R7R8R9R10Polymyxin BMO(H)A-Dab-Thr-Dab-*Dab-Dab-D Phe-Leu-DabDab*ThrColistin (polymyxin E)MO(H)A-Dab-Thr-Dab-*Dab-Dab-D Leu-Leu-DabDab*ThrColistin sulphomethateMO(H)A-sm-Dab-Thr-sm-Dab-*Dab-Sm-Dab-D Leu-Leu-sm--Dab-sm--Dab-*ThrPolymyxin AMO(H)A-Dab-Thr-D Dab-*Dab-Dab-D Leu-Thr-DabDab*ThrPolymyxin MMOADab-Thr-Dab-*Dab-Dab-D Leu-Thr-DabDab*ThrPolymyxin DMO(H)A-Dab-D Ser-Dab-*Dab-Dab-D Leu-Thr-DabDab*ThrCirculin AMOADab-Thr-Dab-*Dab-Dab-D Leu-Ile-DabDab*ThrOctapeptin AOHMDA——Dab-*Dab-Dab-D Leu-Leu-DabDabLeuDeacylcolistin (DAC)Dab-Thr-Dab-*Dab-Dab-D Leu-Leu-DabDab*ThrPolymyxin E nonapeptide (PMEN)Thr-Dab-*Dab-Dab-D Leu-Leu-DabDab*ThrDeacylpolymyxin B (DAPB)Dab-Thr-Dab-*Dab-Dab-D Phe-Leu-DabDab*ThrPolymyxin B nonapeptide (PMBN)Thr-Dab-*Dab-Dab-D Phe-Leu-DabDab*ThrPolymyxin B octapeptide (PMBO)Dab-*Dab-Dab-D Phe-Leu-DabDab*ThrPolymyxin B heptapeptide (PMHP)*Dab-Dab-D Phe-Leu-DabDab*Thr
Polymyxin B is represented by the following formula:
